Obesity is a condition where the energy intake is continuously excessive relative to the energy consumption, thereby causing accumulation of neutral fat in fat cells, resulting in remarkably increased body weight over the standard body weight (Eiji Itagaki, STEP Taisha/Naibunpitsu (STEP metabolism/endocrine), Kaibashobo, 1st. Ed., p. 105, 1998). It is known that excessive accumulation of fat causes, for example, insulin resistance, diabetes, hypertension, hyperlipidemia, and the like, and that combination a plurality of these factors greatly increases the risk of the onset of atherosclerosis. Such a condition is called metabolic syndrome. Further, hypertriglyceridemia and obesity are known to increase the risk of pneumonia, hepatic dysfunction, cancers such as breast cancer, uterine cancer, ovarian cancer, colon cancer, and prostatic cancer, emmeniopathy, arthritis, gout, cholecystitis, gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), sleep apnea syndrome, and the like. It is widely known that diabetes often leads to, onset of, for example, angina pectoris, cardiac insufficiency, stroke, claudication, retinopathy, visual loss, renal insufficiency, neuropathy, skin ulcer, infection, and the like [The Merck Manual of Medical Information, 2nd Home Edition, Merck & Co, 2003].
LCE is an enzyme that exists in the endoplasmic reticulum in cells. In the group of enzymes that catalyze the carbon-chain elongation reaction of fatty acids of chain length C12 or longer, LCE is an enzyme that catalyzes the rate-limiting condensation step. In the mammals, most of fatty acids newly synthesized in vivo have a chain length of C16 to C18. Such long chain fatty acids account for more than 90% of the total fatty acids existing in cells. They are important constituents of the membrane, and are also the basic components of the fatty tissue, the greatest energy conservation organ in animals. Synthesis of new fatty acids most likely takes place in the liver, and such synthesis converts excessive glucose in the body into fatty acids. Glucose is converted by glycolysis into pyruvate. Pyruvate is converted in the mitochondria into citrate, and conveyed to the cytosol. ATP citrate lyase in the cytosol produces fatty acids and acetyl-CoA, a precursor of cholesterol. Acetyl-CoA is carboxylated by acetyl-CoA carboxylase (ACC) to form malonyl-CoA. Fatty acid synthase (FAS), a multifunctional enzyme, elongates fatty acids by 2 carbons, using malonyl-CoA, acetyl-CoA, and NADPH. The main final product of FAS in the rodents is palmitoyl-CoA having a chain length of C16, and LCE elongates the carbon chain of such palmitoyl-CoA by further 2 carbons [J. Biol. Chem., 276 (48), 45358-45366, (2001)]. Excessive acceleration of fatty acid synthesis in vivo is known to cause an increase in neutral fat and the like, which thus is responsible for the accumulation of fats. For example, WO 2005/005665 (Patent Document 1) shows a direct relation between LCE and obesity. Moreover, changes in the mouse FACE (LCE) expression level due to food intake have also been reported (Matsuzaka T. et al., J, Lipid Res., 43(6): 911-920 (2002); Nonpatent Document 1).
LCE is known to exist also in protozoa and nematodes, and be involved in cell proliferation. For example, it has been disclosed that in trypanosomatid protozoa that cause the African trypanosomiasis (vernacular name: African sleeping sickness), long chain fatty acids are synthesized via the fatty acid elongation pathway involving LCE, and that inhibition of intracellular fatty acid elongation reaction affects the proliferation of trypanosomatid protozoa (Lee S. H. et al., Cell, 126: 691-699 (2006); Nonpatent Document 2).
No compound has been known to have LCE inhibitory effect. Meanwhile, the compound of the invention is a piperidine derivative having a sulfonyl group at the 4-position of piperidine (or piperazine), while no compound has been known with the piperidine (or piperazine) moiety forming a bicyclo ring, wherein an aryl group or the like is bound to the nitrogen atom of the piperidine (or piperazine) through a linker.
Patent Document 1: WO 2005/005665 pamphlet
Nonpatent Document 1: J. Lipid Res., 43 (6), pp. 911-920 (2002)
Nonpatent Document 2: Cell, 126: pp. 691-699 (2006)